What do cancer cells have in common with horseshoe crabs and Mr. Spock from Star Trek?
They all depend upon copper. Horseshoe crabs have blue blood because they use copper to transport oxygen in their blood instead of iron (hemocyanin vs hemoglobin). Vulcans’ blood was supposed to be green, for the same reason.
Horseshoe crabs and Vulcans use copper to transport oxygen in their blood. Cancer cells seem to need the metal more than other cells.
To be sure, all our cells need copper. Many human enzymes use the metal to catalyze important reactions, but cancer cells seem to need it more than healthy cells. Manipulating the body’s flow of copper is emerging as an anticancer drug strategy.
A team of scientists from University of Chicago, Emory and Shanghai have developed compounds that interfere with copper transport inside cells. These compounds inhibit the growth of several types of cancer cells, with minimal effects on the growth of non-cancerous cells, the researchers report in Nature Chemistry.
“We’re taking a tactic that’s different from other approaches. These compounds actually cause copper to accumulate inside cells,” says co-senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. Read more
The DNA in our cells is constantly being damaged by heat, radiation and other environmental stresses, and the enzyme systems that repair DNA are critical for life. A particularly toxic form of damage is the covalent attachment of a protein to DNA, which can be triggered by radiation or by anticancer drugs.
Keith Wilkinson, PhD
Emory biochemist Keith Wilkinson and colleagues have a paper this week in the journal eLife probing how a yeast protein called Wss1 is involved in repairing DNA-protein crosslinks. The researchers show how Wss1 wrestles with a protein tag called SUMO on the site of the DNA damage, and how Wss1 and SUMO are involved in the cleanup process.
Three interesting things about this paper:
*The paper grew out of first author Maxim Balakirev’s sabbatical with Wilkinson at Emory. Balakirev’s home base is at the CEA (Alternative Energy and Atomic Energy Commission) in Grenoble, France.
* Since many cancer chemotherapy drugs induce protein-DNA cross links, an inhibitor of cross link repair could enhance those drugs’ effectiveness. On the other side of the coin, mutations in a human gene called Spartan, whose sequence looks similar to Wss1’s, cause premature aging and susceptibility to liver cancer. Whether the Spartan-encoded protein has the same biochemical activity as Wss1 is not yet clear.
*SUMO stands for “small ubiquitin-like modifier”. The eLife digest has an elegant explanation of what’s happening: Read more
Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.
Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.
The results were published Tuesday, August 25 in PLOS Genetics.
“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.
Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.
Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?
The answer: a mutation appears in the RNA first. Read more
As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.
Leslie Kean, MD, PhD
The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.
CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.
The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more
A mutation found in most melanomas rewires cancer cells’ metabolism, making them dependent on a ketogenesis enzyme, researchers at Winship Cancer Institute of Emory University have discovered.
The V600E mutation in the gene B-raf is present in most melanomas, in some cases of colon and thyroid cancer, and in the hairy cell form of leukemia. Existing drugs such as vemurafenib target the V600E mutation — the finding points to potential alternatives or possible strategies for countering resistance. It may also explain why the V600E mutation in particular is so common in melanomas.
Researchers led by Jing Chen and Sumin Kang have found that by promoting ketogenesis, the V600E mutation stimulates production of a chemical, acetoacetate, which amplifies the mutation’s growth-promoting effects. (A feedback mechanism! Screech!)
The results were published Thursday, July 2 in Molecular Cell.
More on this paper here.
Part of the new Winship magazine feature on prostate cancer focuses on a PET imaging probe called FACBC, which was developed by radiologists at Emory. 18F-FACBC (anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid, also called “fluciclovine”) has a lengthening track record in detecting recurrent prostate cancer.
Structure of FACBC, from patent application.
Usually in PET imaging, radioactive glucose is injected into the body, and since cancer cells have a sweet tooth, they take up a lot of the radioactive tracer. But plenty of the tracer also appears in the urine, complicating prostate cancer detection efforts, since the prostate is so close to the bladder. In contrast, FACBC is readily taken up by prostate cancer cells, but doesn’t appear as much in urine.
Because of space considerations, we did not include David Schuster’s description of how FACBC’s utility in prostate was first discovered. Several years ago, he and Mark Goodman had begun investigating the probe’s potential in imaging brain tumors and kidney tumors, and used it with a patient with a large renal mass and many enlarged lymph nodes, as described in the radiology newsletter Aunt Minnie. Read more
The big news from the recent American Society of Clinical Oncology meeting has been largely about immunotherapy drugs, also known as checkpoint inhibitors. These drugs have been shown to be effective in prolonging life in patients with some types of cancer, such as lung cancer and melanoma, but not others, such as colorectal and prostate cancer.
Lab Land asked oncologist Bradley Carthon and immunology researcher Haydn Kissick why. Both Carthon’s clinical work and Kissick’s lab research on prostate cancer are featured in the new issue of Winship magazine, but the prostate feature just touches on checkpoint inhibitors briefly.
Carthon says the reason checkpoint inhibitors haven’t moved the needle with prostate cancer is “likely due to the absence of infiltration of the prostatic tissue by tumor-associated lymphocytes.”
Checkpoint inhibitors are supposed to unleash the immune system, but if the immune cells aren’t in contact with the cancer cells so that the drugs can spur them into action, they won’t help much. Carthon says: “The answer may be to ‘prime’ the prostate with an agent, then introduce the checkpoint inhibitors.” Read more